Macular edema is swelling of retinal macula, and the edema occurs due to a liquid diapedesis from the retinal blood vessels. The blood leaks from weak blood vessel walls and enters into extremely small regions of retinal macula rich in retina cone which is a nerve terminal that detects color and the vision during the day relies on. Next, images become blurred in the center of the central field or right beside the center. The visual acuity decreases progressively for months. Diabetic retinopathy, retinal blood vessel obstruction, ocular inflammation and age-related macular degeneration are all associated with the macular edema. Retinal macula is sometimes damaged by maculatumentia after removal of crystalline lens for the treatment of cataract.
As the conventional therapy of macular edema, photocoagulation by laser irradiation, vitreous surgery and systemic administration, intravitreal administration and sub-Tenon administration of steroid and the like have been performed. The photocoagulation by laser irradiation closes the blood vessel permitting liquid diapedesis, and decreases swelling of macula. However, attention should be paid in laser irradiation to avoid extremely vulnerable fovea. If the fovea should be injured by this surgery, the central visual field may be damaged. Moreover, plural laser surgeries are often required to eliminate swelling. While vitreous surgery is applied to a case for which a laser surgery is ineffective, it is associated with high tissue-invasive potential, sometimes causing problems of post-surgery complications. In addition, the administration of steroid is reported to be useful. While systemic administration of steroid is possible for the treatment of ocular diseases, in general, it often causes side effects which are too severe for ophthalmologic uses. Therefore, intravitreal administration and sub-Tenon administration, which are topical administrations, have also been studied. Although intravitreal administration can solve some problems associated with systemic administration, intravitreal administration of existing ophthalmic compositions can cause ocular hypertension, steroid glaucoma and posterior subcapsular cataract when steroid is administered. Also, intravitreal administration of steroid sometimes causes post-surgery complications. sub-Tenon administration is often used in clinical practice to decrease the tissue-invasive potential of intravitreal administration and burden on patients. While administration of steroid decreases the tissue-invasive potential as compared to vitreous surgery, it is still associated with the problems of post-surgery complications.
Administration by instillation is an administration method with high merit since it has low tissue-invasive potential. Examples of the treatment of ophthalmic diseases by instillation of steroid include use of a 0.1% betamethasone ophthalmic solution for anti-inflammatory diseases (blepharitis, conjunctivitis, keratitis, scleritis, episcleritis, anterior ocular segmentuveitis, postoperative inflammation) in the external eye and the anterior ocular segment. Moreover, WO 2007/025275 describes the possibility of application of instillation and the like of various steroids and corticosteroid antagonists to the treatment of various ophthalmic diseases such as macular degeneration, glaucoma, macular edema, age-related macular degeneration, retina angiogenesis, diabetic retinopathy, iritis, posterior eye segmentuveitis and the like, while decreasing the side effects of steroid. However, only few cases of effectiveness of instillation for macular edema of the retina in clinical practice have been reported, and there is only one report of volume reduction of retinal macular edema by administration of 0.1% betamethasone ophthalmic solution for 2 weeks to one month, 6 times per day (The 43rd Annual Congress of Japanese Retina and Vitreous Society O16-5, 2004). Thus, the treatment of macular edema by eye drop has not been performed.